Systematic Review of Preoperative Prognostic Biomarkers in Perihilar Cholangiocarcinoma.

Perihilar cholangiocarcinoma (pCCA) is an uncommon malignancy with generally poor prognosis. Surgery is the primary curative treatment; however, the perioperative mortality and morbidity rates are high, with a low 5-year survival rate. Use of preoperative prognostic biomarkers to predict survival outcomes after surgery for pCCA are not well-established currently. This systematic review aimed to identify and summarise preoperative biomarkers associated with survival in pCCA, thereby potentially improving treatment decision-making. The Embase, Medline, and Cochrane databases were searched, and a systematic review was performed using the PRISMA guidelines. English-language studies examining the association between serum and/or tissue-derived biomarkers in pCCA and overall and/or disease-free survival were included. Our systematic review identified 64 biomarkers across 48 relevant studies. Raised serum CA19-9, bilirubin, CEA, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and tumour MMP9, and low serum albumin were most associated with poorer survival; however, the cutoff values used widely varied. Several promising molecular markers with prognostic significance were also identified, including tumour HMGA2, MUC5AC/6, IDH1, PIWIL2, and DNA index. In conclusion, several biomarkers have been identified in serum and tumour specimens that prognosticate overall and disease-free survival after pCCA resection. These, however, require external validation in large cohort studies and/or in preoperatively obtained specimens, especially tissue biopsy, to recommend their use.

Day-only elective cholecystectomy: early experience and barriers to implementation in Australia.

BACKGROUND: Day-only laparoscopic cholecystectomy (DOLC) has been shown to be safe and feasible yet has not been widely implemented in Australia. This study explores the introduction of routine DOLC to Westmead Hospital, and highlights the barriers to its implementation. METHODS: Routine day-only cholecystectomy protocol was introduced at Westmead Hospital in 2014. A retrospective review of patients who underwent elective laparoscopic cholecystectomy during a 12-month period in 2014 was compared to a 12-month period in 2018, to examine the changes in practice after implementation of a unit protocol. Data were collected on patient demographics, admission category, outcomes and re-presentations. RESULTS: A total of 282 patients were included in the study, of these 169 were booked as day procedures, with 124 (73%) successfully discharged on the same day. There was a significant increase in the proportion of patients booked as day-only from 2014 to 2018 (48% versus 73%, P < 0.001). Day-only failure rates (unplanned overnight admissions), readmissions and complication rates were comparable between the two periods. The most common reason for unplanned overnight admissions were due to intraoperative findings (n = 28/45). CONCLUSION: Routine DOLC can be adopted in Australian hospitals without compromise to patient safety. Unplanned overnight admission is predominantly due to unexpected surgical pathology and can be reduced by protocols for the use of drains and planned outpatient endoscopic retrograde cholangiopancreatography. Unplanned outpatient review can be minimized by optimizing both intra- and post-operative pain management. Individual surgeon and anaesthetist preferences remain an obstacle to a standardized protocol in the Australian setting.

Paediatric kidney transplants from donors aged 1 year and under: an analysis of the Australian and New Zealand Dialysis and Transplant Registry from 1963 to 2018.

Kidneys from very small donors have the potential to significantly expand the donor pool. We describe the collective experience of transplantation using kidneys from donors aged ≤1 year in Australian and New Zealand. The ANZDATA registry was analysed on all deceased donor kidney transplants from donors aged ≤1 year. We compared recipient characteristics and outcomes between 1963-1999 and 2000-2018. From 1963 to 1999, 16 transplants were performed [9 (56%) adults, 7 (44%) children]. Death-censored graft survival was 50% and 43% at 1 and 5 years, respectively. Patient survival was 90% and 87% at 1 and 5 years, respectively. From 2000 to 2018, 26 transplants were performed [25 (96%) adults, 1 (4%) children]. Mean creatinine was 73 µmol/l ±49.1 at 5 years. Death-censored graft survival was 85% at 1 and 5 years. Patient survival was 100% at 1 and 5 years. Thrombosis was the cause of graft loss in 12% of recipients in the first era from 1963 to 1999, and 8% of recipients in the second era from 2000 to 2018. We advocate the judicious use of these small paediatric grafts from donors ≤1 year old. Optimal selection of donor and recipients may lead to greater acceptance and success of transplantation from very young donors.

Macrophage Coordination of the Interferon Lambda Immune Response.

Lambda interferons (IFN-λs) are a major component of the innate immune defense to viruses, bacteria, and fungi. In human liver, IFN-λ not only drives antiviral responses, but also promotes inflammation and fibrosis in viral and non-viral diseases. Here we demonstrate that macrophages are primary responders to IFN-λ, uniquely positioned to bridge the gap between IFN-λ producing cells and lymphocyte populations that are not intrinsically responsive to IFN-λ. While CD14+ monocytes do not express the IFN-λ receptor, IFNLR1, sensitivity is quickly gained upon differentiation to macrophages in vitro. IFN-λ stimulates macrophage cytotoxicity and phagocytosis as well as the secretion of pro-inflammatory cytokines and interferon stimulated genes that mediate immune cell chemotaxis and effector functions. In particular, IFN-λ induced CCR5 and CXCR3 chemokines, stimulating T and NK cell migration, as well as subsequent NK cell cytotoxicity. Using immunofluorescence and cell sorting techniques, we confirmed that human liver macrophages expressing CD14 and CD68 are highly responsive to IFN-λ ex vivo. Together, these data highlight a novel role for macrophages in shaping IFN-λ dependent immune responses both directly through pro-inflammatory activity and indirectly by recruiting and activating IFN-λ unresponsive lymphocytes.

A systematic review and meta-analysis of cold in situ perfusion and preservation for pancreas transplantation.

BACKGROUND: This study aimed to identify the most effective solution for in situ perfusion/preservation of the pancreas in donation after brain death donors, in addition to optimal in situ flush volume(s) and route(s) during pancreas procurement. METHODS: Embase, Medline and Cochrane databases were utilized (1980-2017). Articles comparing graft outcomes between two or more different perfusion/preservation fluids (University of Wisconsin (UW), histidine-tryptophan-ketoglutarate (HTK) and/or Celsior) were compared using random effects models where appropriate. RESULTS: Thirteen articles were included (939 transplants). Confidence in available evidence was low. A higher serum peak lipase (standardized mean difference 0.47, 95% CI 0.23-0.71, I2 = 0) was observed in pancreatic grafts perfused/preserved with HTK compared to UW, but there were no differences in one-month pancreas allograft survivals or early thrombotic graft loss rates. Similarly, there were no significant differences in the rates of graft pancreatitis, thrombosis and graft survival between UW and Celsior solutions, and between aortic-only and dual aorto-portal perfusion. CONCLUSION: UW cold perfusion may reduce peak serum lipase, but no quality evidence suggested UW cold perfusion improves graft survival and reduces thrombosis rates. Further research is needed to establish longer-term graft outcomes, the comparative efficacy of Celsior, and ideal perfusion volumes.

A systematic review and meta-analysis of cold in situ perfusion and preservation of the hepatic allograft: Working toward a unified approach.

The efficacy of cold in situ perfusion and static storage of the liver is a possible determinant of transplantation outcomes. The aim of this study was to determine whether there is evidence to substantiate a preference for a particular perfusion route (aortic or dual) or perfusion/preservation solution in donation after brain death (DBD) liver transplantation. The Embase, MEDLINE, and Cochrane databases were used (1980-2017). Random effects modeling was used to estimate effects on transplantation outcomes based on (1) aortic or dual in situ perfusion and (2) the use of University of Wisconsin (UW), histidine tryptophan ketoglutarate (HTK), Celsior, and/or Institut Georges Lopez-1 (IGL-1) solutions for perfusion/preservation. A total of 22 articles were included (2294 liver transplants). The quality of evidence ranged from very low to moderate Grading of Recommendations, Assessment, Development and Evaluations score. Meta-analyses were conducted for 14 eligible studies. Although there was no difference in the primary nonfunction (PNF) rate, a higher peak alanine aminotransferase (ALT) was recorded in dual compared with aortic-only UW-perfused livers (standardized mean difference, 0.24; 95% confidence interval, 0.01-0.47); a back-table portal venous flush was undertaken in the majority of aortic-only perfused livers. There were no relevant differences in peak enzymes, PNF, thrombotic graft loss, biliary complications, or 1-year graft survival in comparisons between dual-perfused livers using UW, HTK, Celsior, or IGL-1. In conclusion, there is no significant evidence that aortic-only perfusion of the DBD liver compromises transplantation outcomes, and it may be favored because of its simplicity. However, there is currently insufficient evidence to advocate for the use of any particular perfusion/preservation fluid over the others. Liver Transplantation 23 1615-1627 2017 AASLD.

The Abdominal Reapproximation Anchor Device.

INTRODUCTION: Achieving primary fascial closure after damage control laparostomy can be challenging. A number of devices are in use, with none having yet emerged as best practice. In July 2013, at Westmead Hospital, we started using the abdominal reapproximation anchor (ABRA; Canica Design, Almonte, Ontario, Canada) device. We report on our experience. METHODS: A retrospective review of medical records for patients who had open abdomens managed with the ABRA device between July to December 2013 was done. Data extracted included age, sex, body mass index (BMI), reason for the open abdomen, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, number of laparostomies prior to ABRA placement, duration of placement, device complications, length of hospital and intensive care unit (ICU) stay, and outcomes. RESULTS: Four cases of open abdomens managed using the ABRA device were identified, with 3 a consequence of intra-abdominal sepsis and 1 a consequence of penetrating trauma. Mean BMI was 33.5 kg/m2, APACHE II score was 14.5, duration with open abdomen prior to ABRA placement was 11.75 days, duration with ABRA in situ was 9 days, duration of hospital stay was 64.25 days, and ICU stay was 37.75 days. Three patients (75%) achieved fascial closure, and 1 achieved skin closure. No incidences of enterocutaneous fistulae occurred. CONCLUSION: The ABRA is a unique emerging alternative to aid in achieving fascial closure in patients managed with open abdomens. Our case series demonstrates that it can be used effectively in selected patients. Studies are needed to compare its efficacy with more traditional methods.

Index cholecystectomy in grade II and III acute calculous cholecystitis is feasible and safe.

BACKGROUND: According to the Tokyo Guidelines, recommendation on management of moderate and severe cholecystitis are cholecystostomy in severe cases and either cholecystostomy or emergency cholecystectomy in moderate cases depending on surgical experience. The rationale for this is that percutaneous cholecystostomy is a short procedure while laparoscopic cholecystectomy may be associated with a larger physiological insult. The aim of this study was to determine the safety and efficacy of cholecystectomy in moderate and severe acute calculous cholecystitis (ACC) at our institution. METHODS: A retrospective review of patients presenting to Westmead Hospital with ACC between 2011 and 2012 was performed. Patients were classified according to the Tokyo Guidelines and only grade II and grade III patients were included. Clinical and complication details were recorded from the clinical notes. RESULTS: Of the 84 patients, 60 had grade II and 24 had grade III ACC. The mean age was 52 years and 59% were female. In both groups, index cholecystectomy was performed in 88% of patients. None of the grade II ACC patients and three (12%) of grade III ACC underwent cholecystostomy. Length of stay (5 versus 12, P < 0.001) and conversion rate (2% versus 27%, P = 0.006) was higher in the grade III group. There were no deaths in patient who underwent surgery in either group. Severe complications were not significantly different (2% versus 9%, P = 0.219). CONCLUSION: Index cholecystectomy is feasible with low morbidity and no mortality even in severe ACC. Emergency cholecystectomy in the setting of severe cholecystitis appear to be safe and technically feasible option.

Renal transplantation: better fat than thin.

BACKGROUND: Obesity has been a relative contraindication for renal transplantation. This study evaluates the impact of pretransplant body mass index (BMI) on renal transplant outcomes in a single institution in the era of modern immunosuppression. MATERIALS AND METHODS: A 10-y retrospective analysis was undertaken of 454 consecutive patients who received a renal transplant at Westmead Hospital from January 1, 2001 to December 31, 2010. The role of pretransplant BMI on patient survival, graft survival, surgical complications, and postoperative complications was studied. RESULTS: The mean age of transplant of this study population was 45.4 ± 13.0 y. Live donation rate was 53.5%, and 60.6% were male. The median preoperative BMI was 25.6 (range, 14.3-51.4). One-year and 5-y patient survival were 97.4% and 86.6%, respectively, whereas 1-y and 5-y death-censored graft survival were 97.1% and 91.9%, respectively. Patients with BMI >30 did not exhibit any significant difference in survival or graft failure but had higher surgical wound infection rates (hazard ratio 3.95, P < 0.01). Patients with preoperative BMI <18.5 were associated with a six-fold increase in both death and death-censored graft failure (P < 0.01). CONCLUSIONS: Pretransplant obesity increases wound infection but is not a contraindication to renal transplantation. Future prospective studies are required to further define the impact of low preoperative BMI <18.5.

Significant elevations of serum lipase not caused by pancreatitis: a systematic review.

BACKGROUND: Many authors advocate lipase as the preferred serological test for the diagnosis of pancreatitis and a cut-off level of three or more times the upper limit of normal (ULN) is often quoted. The literature contains no systematic review that explores alternative causes of a lipase level over three times as high as the ULN. Such a review was therefore the objective of this study. METHODS: The EMBASE and MEDLINE databases (1985 to August 2013) were searched for all eligible articles. Predetermined data were extracted and independently analysed by two reviewers. RESULTS: In total, data from 58 studies were included in the final analysis. The following causes other than pancreatitis of lipase levels exceeding three times the ULN were found: reduced clearance of lipase caused by renal impairment or macrolipase formation; other hepatobiliary, gastroduodenal, intestinal and neoplastic causes; critical illness, including neurosurgical pathology; alternative pancreatic diagnoses, such as non-pathological pancreatic hyperenzymaemia, and miscellaneous causes such as diabetes, drugs and infections. CONCLUSIONS: A series of differential diagnoses for significant serum lipase elevations (i.e. exceeding three times the ULN) has been provided by this study. Clinicians should utilize this knowledge in the interpretation and management of patients who have lipase levels over three times as high as the ULN, remaining vigilant for an alternative diagnosis to pancreatitis. The medical officer should be aware of the possibility of incorrect diagnosis in the asymptomatic patient.

Systematic review and meta-analysis of laparoscopic versus open distal gastrectomy.

BACKGROUND: Laparoscopic distal gastrectomy has been increasingly utilized in the treatment of gastric adenocarcinoma. This study aims to compare the morbidity/mortality and postoperative outcomes of laparoscopic-assisted versus open distal gastrectomy since 2000. METHODS: A comprehensive search of MEDLINE and EMBASE was conducted including studies published between 2000 and present. RESULTS: Seventeen studies with a total of 7,109 distal gastrectomies (3,496 lap vs 3,613 open) were included. Across all studies, postoperative morbidity rates for laparoscopic gastrectomy were lower than that of open [median (range) 10 (0-36) % vs 17 (0-43) %]. Meta-analysis of postoperative morbidity rates in prospective studies only yielded pooled odds ratio of 0.52 (95 % CI 0.33-0.81) (P = 0.004). In-hospital mortality rates were comparable between the two (range: laparoscopic 0-3.3 vs open 0-6.7 %). The long-term oncological outcomes of resection were difficult to analyze given variable reporting but appeared similar between the two. Meta-analysis of prospective studies showed that laparoscopic-assisted distal gastrectomy was associated with significantly shorter hospital length of stay [standard mean difference (SMD) = -0.78 (95 % CI = -1.0 to -0.56)], comparable intraoperative bleeding [SMD = 0.64 (95 % CI = -1.3-0.0430) P = 0.066] and longer operative time compared to open gastrectomy [1.9 (95 % CI 0.05-3.8) P = 0.045, with P < 0.001]. CONCLUSION: This study supports the use of laparoscopic-assisted distal gastrectomy for treatment of gastric adenocarcinoma with evidence of comparable, if not better, short-term postoperative parameters when compared to open distal gastrectomy. The long-term oncological outcomes appear similar but may require more evaluation.

A systematic review of a liver-first approach in patients with colorectal cancer and synchronous colorectal liver metastases.

BACKGROUND: Since the liver metastases rather than the colorectal cancer itself is the main determinant of patient's survival, the 'Liver-First Approach (LFA)' with upfront chemotherapy followed by a hepatic resection of colorectal liver metastases (CLM) and finally a colorectal cancer resection was proposed. The aim of this review was to analyse the evidence for LFA in patients with colorectal cancer and synchronous CLM. METHODS: A literature search of databases (MEDLINE and EMBASE) to identify published studies of LFA in patients with colorectal cancer and synchronous CLM was undertaken focussing on the peri-operative regimens of LFA and survival outcomes. RESULTS: Three observational studies and one retrospective cohort study were included for review. A total of 121 patients with colorectal cancer and synchronous CLM were selected for LFA. Pre-operative chemotherapy was used in 99% of patients. One hundred and twelve of the initial 121 patients (93%) underwent a hepatic resection of CLM. In total, 60% had a major liver resection and the R0 resection rate was 93%. Post-operative morbidity and mortality after the hepatic resection were 20% and 1%, respectively. Ultimately, 89 of the initial 121 (74%) patients underwent a colorectal cancer resection. Post-operative morbidity and mortality after a colorectal resection were 50% and 6%, respectively. The median overall survival was 40 months (range 19-50) with a recurrence rate of 52%. CONCLUSIONS: Current evidence suggests that LFA is safe and feasible in selected patients with colorectal cancer and synchronous CLM. Future studies are required to further define patient selection criteria for LFA and the exact role of LFA in the management of synchronous CLM.

Use of pre-operative steroids in liver resection: a systematic review and meta-analysis.

BACKGROUND: By attenuating the systemic inflammatory response to major surgery, the pre-operative administration of steroids may reduce the incidence of complications. METHODS: A systematic review was conducted to identify randomized controlled trials (RCT) comparing pre-operative steroid administration with placebo during a liver resection. Meta-analyses were performed. RESULTS: Five RCTs were identified including a total of 379 patients. Pre-operative steroids were associated with statistically significant reductions in the levels of serum bilirubin and interleukin 6 (IL-6) on post-operative day one. There was a trend towards a lower incidence of post-operative complications and prothrombin time (PT), but this did not reach statistical significance. CONCLUSION: Pre-operative steroids may be associated with a clinically significant benefit in liver resection.

Hepatic resection for metastatic melanoma: a systematic review.

Melanoma metastatic to the liver has a very poor prognosis, and has traditionally been treated using systemic chemotherapy with limited efficacy. Surgery is increasingly being explored as a therapeutic option for melanoma liver metastases, with varying levels of success. A systematic review was undertaken to explore the short-term and long-term outcomes associated with hepatectomy for melanoma metastases, in addition to identifying prognostic factors favouring increased survival. All eligible studies were identified through an electronic search of Medline and Embase (January 1990-March 2013). Each study was independently analysed by two reviewers, with relevant data extracted and tabulated according to predetermined criteria. Thirteen studies were selected that fulfilled the selection criteria, with a total of 551 patients undergoing hepatic resection for melanoma metastases. Metastases to the liver occurred at a median interval of 54 months. The median perioperative morbidity and mortality were 10% (range 0-28.6%) and 0% (range 0-7.1%), respectively. The median overall survival for operative patients was 24 months, with median survival being greater in the R0 resection group (25 months; range 9.5-65.6 months) compared with the R1/2 resection group (16 months; range 11.7-29 months). Overall median 1-, 3- and 5-year survival rates were 70% (range 39-100%), 36% (range 10.2-53%) and 24% (range 3-53%), respectively. Positive prognostic factors may include single hepatic metastases, a longer time to development of hepatic metastases and R0 resection. Hepatic resection for metastatic melanoma might confer a distinct survival benefit in a select group of patients, although disease recurrence is the norm.

The volume effect in liver surgery--a systematic review and meta-analysis.

BACKGROUND: There is an inverse relationship between hospital and surgeon volume and mortality in many types of complex surgery. The aim of this paper is to investigate the volume effect on outcomes of liver surgery. METHODS: A systematic review and meta-analysis was performed. A literature search was conducted using Medline and EMBASE from 1995 to 2012. A random effects model was used. RESULTS: Seventeen studies were selected for detailed analysis. Definition of a high-volume institution varied from 2 to more than 33 procedures per year. The pooled odds ratio of mortality rate in low- vs high-volume centres was 2.0 [95 % confidence interval (CI), 1.6-2.4; P < 0.001]. Some studies divided centres into more than two groups and compared the highest and lowest volume groups. The pooled odds ratio of mortality rate for this comparison type was 3.2 (95 % CI, 1.7-5.8; P < 0.001). Funnel plots suggest possible publication bias. There was inadequate data to compare morbidity. Only two of seven studies demonstrated a shorter length of stay in the high-volume centres. There was no convincing volume effect on long-term survival. CONCLUSIONS: This study suggests a strong relationship between volume and perioperative mortality. No difference in morbidity, length of stay or survival was demonstrated.